Inflammation plays a fundamental role in host defenses and the progression of immune-mediated disease. The inflammatory response is initiated in response to injury (e.g. trauma, ischemia, and foreign particles) and infection (e.g. bacterial or viral infection) by multiple events, including chemical mediators (e.g. cytokines and prostaglandins) and inflammatory cells (e.g. leukocytes). It is characterized by increased blood flow to the tissue, causing pyrexia, erythema, induration and pain.
A delicate well-balanced interplay between the humoral and cellular immune elements in the inflammatory response enables the elimination of harmful agents and the initiation of the repair of damaged tissue. When this delicately balanced interplay is disrupted, the inflammatory response may result in considerable damage to normal tissue and may be more harmful than the original insult that initiated the reaction. In these cases of uncontrolled inflammatory responses, clinical intervention is needed to prevent tissue damage and organ dysfunction. Diseases such as rheumatoid arthritis, osteoarthritis, Crohn's disease, asthma, allergies, septic shock syndrome, atherosclerosis, inflammatory bowel disease among other clinical conditions are characterized by chronic inflammation.
Cytokines, especially IL-1β, IL-6, IL-8 and TNF-α, play an important role in the inflammatory process.
TNF-α, a pleiotropic cytokine, is produced mainly by macrophages, but it may be produced by other types of cells also. TNF-α demonstrates beneficial as well as pathological activities. It has both growth stimulating effects and growth inhibitory properties, besides being self-regulatory. The beneficial functions of TNF-α include maintaining homeostasis by regulating the body's circadian rhythm, mounting an immune response to bacterial, viral, fungal and parasitic infections, replacing or remodeling injured tissue by stimulating fibroblast growth and as the name suggests, killing certain tumors.
Although TNF-α plays a critical role in innate and acquired immune responses, inappropriate production of TNF-α can produce pathological changes resulting in chronic inflammation and tissue damage. TNF-α has been shown to play a crucial role in the pathogenesis of many chronic inflammatory disease such as inflammatory bowel disease, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, osteoarthritis, refractory rheumatoid arthritis, chronic non-rheumatoid arthritis, osteoporosis/bone resorption, coronary heart disease, vasculitis, ulcerative colitis, psoriasis, adult respiratory distress syndrome, diabetes, skin delayed type hypersensitivity disorders and Alzheimer's disease. Interleukin-1 (IL-1) is an important part of the innate immune system, which regulates functions of the adaptive immune system. The balance between IL-1 and IL-1 receptor antagonist (IL-1ra) in local tissues influences the possible development of an inflammatory disease and resultant structural damage. In the presence of an excess amount of IL-1, inflammatory and autoimmune disorders may be developed in joints, lungs, gastrointestinal tract, central nervous system (CNS) or blood vessels.
Among various inflammatory disorders, rheumatoid arthritis (RA) is an autoimmune disorder. RA is a chronic, systemic, articular inflammatory disease of unknown etiology. In RA, the normally thin synovial lining of joints is replaced by an inflammatory, highly vascularized, invasive fibrocollagenase tissue (pannus), which is destructive to both cartilage and bone. Areas that may be affected include the joints of the hands, wrists, neck, jaw, elbows, knee, feet and ankles. Cartilage destruction in RA is linked to aberrant cytokines and growth factor expression in the affected joints.
Two clinically important cytokines released in the synovium are IL-1β and TNF-α. TNF-α can upregulate its own expression as well as facilitate the expression of other genes implicated in RA, including IL-1β, IL-6, IL-8, cyclooxygenase-2 (COX-2), inducible nitric oxide synthetase (iNOS), intercellular adhesion molecule 1 (ICAM-1), vascular-cell adhesion molecule 1 (VCAM-1), and E-Selectin. This type of positive regulatory loop may amplify and perpetuate local inflammatory responses. Therefore, the inappropriate or over-expression of TNF-αleads to a coordinated increase in the expression of many genes whose products mediate inflammatory and immune responses and thereby lead to the clinical manifestations of RA.
The recruitment and retention of leukocytes is a critical event in the pathogenesis of all chronic inflammatory disorders including RA. Moreover, the adhesion of circulating leukocytes, especially monocytes, to vascular endothelium is also a crucial event in the development of atherosclerosis. This process depends on the interaction between the adhesion molecules expressed on the surface of endothelial cells such as ICAM-1, VCAM-1, and E-Selectin and their cognate ligands on leukocytes. Hence, ICAM-1, VCAM-1, and E-Selectin are responsible for the recruitment of inflammatory cells, such as neutrophils, eosinophils, and T lymphocytes, from the circulation to the site of inflammation. These adhesion proteins are normally at low level on the endothelial cell surface but are greatly induced by various proinflammatory cytokines such as TNF-α.
Another inflammatory disorder, inflammatory bowel disease (IBD) is a group of disorders that cause the inflammation of the intestines. The inflammation lasts for a long time and usually relapses. The two major types of IBD disorders are Crohn's disease and ulcerative colitis.
Crohn's disease occurs when the lining and wall of the intestines becomes inflamed resulting in the development of ulcers. Although Crohn's disease can occur in any part of the digestive system, it often occurs in the lower part of the small intestine where it joins the colon.
Ulcerative colitis is a chronic inflammatory disease of unknown etiology afflicting the large intestine. The course of the disease may be continuous or relapsing, mild or severe. The earliest lesion is an inflammatory infiltration with abscess formation at the base of the crypts of Lieberkuhn. Coalescence of these distended and ruptured crypts tends to separate the overlying mucosa from its blood supply, leading to ulceration. Signs and symptoms of the disease include cramping, lower abdominal pain, rectal bleeding, and frequent, loose discharges consisting mainly of blood, pus, and mucus with scanty fecal particles. A total colectomy may be required for acute, severe or chronic, unremitting ulcerative colitis.
Yet another inflammatory disorder is atherosclerosis. Atherosclerosis is a disease affecting arterial blood vessels. It is a chronic inflammatory response in the walls of arteries, in large part due to the deposition of lipoproteins (plasma proteins that carry cholesterol and triglycerides). It is commonly referred to as “hardening” or “furring” of the arteries. It is caused by the formation of multiple plaques within the arteries resulting in the inflammation of the arteries.
The most common therapy for treatment of inflammatory disorders involves use of non-steroidal anti-inflammatory drugs (NSAIDs) e.g. naproxen, diclofenac, ibuprofen to alleviate symptoms such as pain. However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions. Moreover, NSAIDs merely treat the symptoms of disorder and not the cause.
When patients fail to respond to NSAIDs, other drugs such as methotrexate, gold salts, D-penicillamine and corticosteroids are used. These drugs also have significant toxic effects.
Monoclonal antibody drugs such as infliximab, etanercept and adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.
Hence, there is a need for the development of improved and alternative medicaments with reduced side effects for the prevention and treatment of inflammatory disorders caused by increased IL-1 and TNF-α.
Herbs have been known and used throughout the world for treatment of many conditions. There is evidence that products derived from plants have potential pharmacological and therapeutic effects on mammals and tend to have less deleterious side effects than synthetic drugs.
The present invention describes a novel herbal composition, which comprises extract of flowering and fruiting heads of the plant, Sphaeranthus indicus. The composition can be used for treatment of various inflammatory disorders with minimal side effects. Sphaeranthus indicus is a common weed found in rice fields. It belongs to the family Asteraceae and in the literature of Ayurveda, it is known as mahamundi or gorakhmundi. The plant, available throughout India, is a branched herb with purple flowers. It is used in hepatic and gastric disorders. It is used in folk medicine as a remedy for various ailments including dysentery, pain in the uterus and vagina, diseases of the chest, purification and enrichment of blood, urinary tract infections, wound healing and several other diseases. A polyherbal formulation “RV-08”, containing Sphaeranthus indicus has been developed with a view to counteract immunodeficient disorders (Indian Journal of Pharmacology, 33, 454-55, (2001)). Isolation of a new sesquiterpene glycoside, sphaeranthanolide, from the flowers of Sphaeranthus indicus has been reported. The isolated compound, Sphaeranthanolide, exhibited immunostimulating activity. (Phytochemistry, 29(8), 2573-76, (1990)).
Immunomodulatory activity of methanol extract of flower-heads of Sphaeranthus indicus has been reported (Ars Pharmaceutica 45:3; 281-91, (2004)).
The aqueous extract obtained from roots of Sphaeranthus indicus is reported to be moderately active in down-regulating Propionibacterium acnes induced TNF-α and IL-8 production. Sphaeranthus indicus caused a smaller, still significant suppression of reactive oxygen species (Phytomedicine, 10(1), 34-38, (2003)).
To our knowledge, there is no report of any medicament containing extract of flowering and fruiting heads of Sphaeranthus indicus for treatment of inflammatory disorders. To overcome the problems of side effects of present line of treatment, such as allergy induction, activation of latent tuberculosis, myelosuppression, increased risk of cancer and congestive heart disease, associated with the prior art compositions, the present inventors have prepared a novel herbal composition effective against inflammation, having inhibitory activity against TNF-α, interleukins (IL-1, IL-6, IL-8) and the expression of intercellular adhesion molecule 1 (ICAM-1), vascular-cell adhesion molecule 1 (VCAM-1), and E-Selectin. The compositions of the present invention can also be used in combination with at least one other anti-inflammatory agent.